The extracellular matrix protein Fibronectin (FN) plays an important role in cell contractility, differentiation, growth, adhesion, and migration. The 12th -14th Type III repeats of FN (FNIII 12-14), also referred to as the Heparin-II domain, comprise a highly promiscuous growth factor (GF) binding region. This binding domain aids in cellular signaling initiated from the ECM. Additionally, FN has the ability to assemble into fibrils under certain conditions, mostly observed during cell contractile processes such as those that initiate due to upregulation of Transforming Growth Factor Beta 1 (TGF-β1) [1], [2]. Previous work from our lab has shown that self-assembly of FN into insoluble fibrils is crucial for Epithelial-Mesenchymal Transition (EMT) [3]. The transition from epithelial to mesenchymal cell type has been implicated as an early event in tumor formation and breast cancer. We were previously able to find that upregulation of FN fibrils drive EMT through contractility due to the increase of the GF latent TGF-β complex concentration at the cell membrane [3]. The challenge in the current work is to exploit the role of Heparin-II binding domain and to concentrate growth factors of interest, such as those that are pro-EMT or anti-EMT at the signaling sites of the cell membrane. Initially, we investigated the localization of the fragments FNIII 12-14 delivered to cell membrane using FITC conjugated protein. We then investigated the effects of exogenous FNIII 12-14 on EMT using breast epithelial cells (MCF10A) in the presence or absence of TGF-β1 to determine whether FNIII 12-14 alters EMT signaling. Quantification of mRNA expression, for EMT markers such as Slug, Snail, Twist, and ZEB1 were analyzed. Results showed that dosage increase of FNIII 12-14 appears to inhibit EMT transcription factors. This study will develop a new understanding of disease and gene control using ECM proteins. The exploitation of ECM natural protein interactions could become a new method in turning on/off genes of interest. While we are currently investigating this as a mechanism of blocking EMT, it could also have implications in wound healing, fibrosis, and tissue engineering, where EMT is an important aspect of the physiologic progression.